Rap1 (Ras-proximate-1) is a small G protein in the Ras superfamily. Like all G proteins, Rap1 is activated when bound GDP is exchanged for GTP. Rap1 is targeted to lipid membranes by the covalent attachment of lipid moieties to its carboxyl terminus. Movement of Rap1 from endosomal membranes to the plasma membrane upon activation has been reported in several cell types including Jurkat T cells and megakaryocytes. On activation, Rap1 undergoes conformational changes that facilitate recruitment of a variety of effectors, triggering it's participation in integrin signaling, ERK activation, and others.
Stork PJ, Dillon TJ.; ''Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions.''; PubMedEurope PMCScholia
Schultess J, Danielewski O, Smolenski AP.; ''Rap1GAP2 is a new GTPase-activating protein of Rap1 expressed in human platelets.''; PubMedEurope PMCScholia
Hoffmeister M, Riha P, Neumüller O, Danielewski O, Schultess J, Smolenski AP.; ''Cyclic nucleotide-dependent protein kinases inhibit binding of 14-3-3 to the GTPase-activating protein Rap1GAP2 in platelets.''; PubMedEurope PMCScholia
Polakis PG, Rubinfeld B, Evans T, McCormick F.; ''Purification of a plasma membrane-associated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells.''; PubMedEurope PMCScholia
Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, Chen EJ, Bany IA, Mochizuki N, Ashbacher A, Matsuda M, Housman DE, Graybiel AM.; ''A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia.''; PubMedEurope PMCScholia
Kurachi H, Wada Y, Tsukamoto N, Maeda M, Kubota H, Hattori M, Iwai K, Minato N.; ''Human SPA-1 gene product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2. Segregate expression profiles from a rap1GAP gene product.''; PubMedEurope PMCScholia
Lafuente E, Boussiotis VA.; ''Rap1 regulation of RIAM and cell adhesion.''; PubMedEurope PMCScholia
Cook SJ, Rubinfeld B, Albert I, McCormick F.; ''RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts.''; PubMedEurope PMCScholia
Hu CD, Kariya Ki, Kotani G, Shirouzu M, Yokoyama S, Kataoka T.; ''Coassociation of Rap1A and Ha-Ras with Raf-1 N-terminal region interferes with ras-dependent activation of Raf-1.''; PubMedEurope PMCScholia
Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, Housman DE, Graybiel AM.; ''CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation.''; PubMedEurope PMCScholia
Lafuente EM, van Puijenbroek AA, Krause M, Carman CV, Freeman GJ, Berezovskaya A, Constantine E, Springer TA, Gertler FB, Boussiotis VA.; ''RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion.''; PubMedEurope PMCScholia
Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.
Rap1 signalling is terminated by the hydrolysis of bound GTP to GDP. The intrinsic GTPase activity of Rap1 is greatly enhanced by GTP-ase activating proteins (GAPs).
Signals from agonist receptors (such as GPVI) trigger the production of PIP3, DAG, cAMP and elevated Ca++ levels. This leads to the activation and translocation of active Rap1-GTP to the plasma membrane. Rap-GEFs stimulate the replacement of GDP for GTP, activating Rap1. Several Rap1 GEFs have been identified enabling Rap1 to respond to diverse stimuli. CalDAG-GEFs activate Rap1 in response to calcium and DAG, downstream of Phospholipase C. EPAC (exchange proteins directly activated by cAMP) GEFs are activated by binding cAMP.
cGMP and cAMP dependent protein kinases (PKG and PKA respectively) phosphorylate the Rap1 GTPase activating RAP1GAP2 at serine 7 (Schultess et al. 2007). This reduces the binding of inhibitory 14-3-3 proteins to RAP1GAP2.
RAP1GAP2 binds 14-3-3 proteins beta and zeta, inhibiting its GAP activity for Rap1. This effect is diminished by Ser-7 phosphorylation of RAP1GAP2 by cGMP- and cAMP-dependent protein kinases (PKG and PKA respectively), which inhibits the binding of 14-3-3 proteins beta and zeta to Rap1GAP2. 14-3-3 binding does not appear to alter the GTPase-activating function of Rap1GAP2 in vitro, but attenuates Rap1GAP2 mediated inhibition of cell adhesion (Hoffmeister et al. 2008).
EPACs (exchange proteins directly activated by cAMP) are Rap1 GEFs that are activated by direct binding of cAMP (cyclic adenosine monophosphate). cAMP-GEFI (EPAC1) is widely expressed, while cAMP-GEFII (EPAC2) is enriched in brain and adrenal tissue. Both are selective for Rap1. A role of EPACs has been proposed for Rap1-dependent cell adhesion to laminin in both epithelial and red blood cells, and in the regulation of vascular endothelial barrier function.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=392517
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